New research offers a blueprint for tackling addiction

Washington, D.C. - Meaghan Creed is the 2017 grand prize winner of the inaugural Science & PINS Prize for Neuromodulation, for research that helps make sense of the poorly understood biology underlying addiction. The findings, described in her prize winning essay, "Toward a targeted treatment for addiction," could eventually pave the way to desperately needed therapeutic options for substance abuse disorders.

One major challenge that has hindered scientists from developing effective treatments for neuropsychiatric conditions like addiction is that diagnoses are based on behavior, rather than on observable changes in the brain (including neuron loss, or other structural alterations). As such, researchers continue to be puzzled by how disruptions in brain function can lead to addiction.

To address this knowledge gap, Creed and her colleagues at the University of Geneva focused their attention on neural circuits, or clusters of neurons that work together - connected by synapses (structures that allow nerve cells to communicate with each other). Synapses are modified upon exposure to addictive compounds, further promoting drug-seeking behaviors. What's more, addictive agents induce long-lasting changes in the brain's wiring that persist after they leave the body, which is why even after long periods of abstinence, patients with addiction still experience cravings, and often relapse.

Equipped with a basic understanding that drug-based addiction interventions are typically unsuccessful (likely because they have systemic side effects that may change the function of many neural circuits), the team took a more targeted approach - using optogenetics (the use of light to control neurons) - to selectively reverse symptoms of addiction in rodents.

Since optogenetics is not ready for immediate use in patients, the team developed a novel, "optogenetically-inspired" form of deep-brain stimulation (DBS) by combining electrical stimulation with pharmacology. Her method offers a potential blueprint for correcting neural circuit dysfunction after prolonged use of addictive agents.

Creed and her colleagues in the lab of Christian Lüscher at the University of Geneva determined how synapses in the reward system are modified by cocaine exposure in mice, and successfully established causal links between such synaptic alterations and drug-adaptive behavior. They treated the animals with cocaine for five days and measured subsequent locomotor responses to verify addictive behavior.

Interestingly, while the use of optogenetics alone reversed the signs and symptoms of addiction, initial attempts to mimic this outcome using DBS showed no effect. The researchers determined the non-specific nature of the electrical stimulation associated with DBS activated a range of different neurons, which in turn failed to reinstate healthy cross-talk between neurons involved in the brain's reward system. The team then fine-tuned their method by adding a dopamine D1 receptor inhibitor along with DBS, causing the animals to behave as if they had never received cocaine.

Creed says the method "has important advantages over conventional DBS." The effects of conventional DBS are transient, while one 10 minute session of optogenetically-inspired DBS eliminated drug-seeking behavior in mice for over a week. Creed was also able to deduce the synaptic mechanism of optogenetically-inspired DBS from her experiments, unlike the mechanisms of conventional DBS that remain incompletely understood, and likely contribute to the procedure's variable efficacy and off-target side effects.

In her award-winning essay, which will be published in the 4 August issue of Science, Creed confirms the role played by neurons called D1-MSNs addiction, based on her observation that repairing their ability to transmit signals to the ventral palladium (referred to as the pleasure- or reward-seeking region of brain) abolished behavioral sensitization to cocaine. This result hints that the ventral palladium may be a promising target for future neuromodulation therapies.

"Meaghan Creed's work has used cutting-edge technologies to develop a potential therapy for the pressing problem of addiction. Starting with mice and optogenetics, she discovered the susceptible brain circuits, then arrived at a protocol combining pharmaceuticals and deep brain stimulation that could be applicable to humans," said senior science editor Dr. Pamela Hines. "Dr. Creed's research shows how new approaches can forge pathways of success for addressing recalcitrant problems."

"Our results raise the intriguing possibility that we may be able to tailor stimulation protocols to treat specific behavioral symptoms of addiction depending on patients' needs," said Creed, who earned her Ph.D. from University of Toronto and completed post-doctoral training at the University of Geneva.

Creed hopes her unique method improves on existing treatments for addictive disorders by providing continued benefits that keep craving symptoms at bay. Next steps will include testing the neuromodulation protocols developed in other animal models, before they can be considered for clinical applications.

Importantly, Creed notes that optogenetically-inspired DBS may not be limited to addiction. "It is my ultimate goal that we will be able to develop specific neuromodulatory interventions that can normalize circuit function and treat behavioral symptoms of other conditions characterized by dysfunction of the reward system, such as ADHD, bipolar disorder or depression, " said Creed, the first-ever winner of the prize, and curremt assistant professor at the University of Maryland School of Medicine.

"The Science & PINS Prize for Neuromodulation aims to highlight researchers' accomplishments related to alteration of neural activity through specific stimuli. This field of study has great potential, but there are many deep questions that challenge our ability to develop successful therapies for patients affected by neurological conditions," said Science editor-in-chief Dr. Jeremy Berg. "Science is honored to partner with PINS, to help recognize scientists who are working in this exciting and rapidly developing area."

Established in 2016, the Science & PINS Prize for Neuromodulation is a highly competitive prize which honors scientists for their excellent contributions to neuromodulation research - awarded annually for outstanding research as described in a 1,500 word essay based on research performed in the past three years. The winner is awarded $25,000 and publication of his or her essay in Science. The award is announced and presented at a ceremony in September 2017. PINS will provide financial support to allow the grand prize winner and finalist to attend the ceremony.

Creed and finalist Raag Airan will be recognized at the 8th Neuromodulation Conference in Jinan, Shandong Province of China on 2 September at 9:30 a.m., during an award ceremony that will be held in the First Academic Session. The conference is organized by the Chinese Neuromodulation Society.

2017 Grand Prize Winner

Meaghan Creed, for her essay "Toward a targeted treatment for addiction." Creed received her H.B.Sc. and Ph.D. degrees from the University of Toronto and completed post-doctoral training at the University of Geneva. As an assistant professor at the University of Maryland School of Medicine, she is investigating the cellular and synaptic basis of bipolar and substance use disorders with the goal of developing circuit-based interventions for these conditions.

Finalist Raag Airan, for his essay "Neuromodulation with nanoparticles." Airan received his undergraduate degrees in mathematics and physics from MIT, and his M.D. and Ph.D. in Bioengineering from Stanford University. He then completed his clinical residency in radiology and fellowship in neuroradiology at Johns Hopkins University. Dr. Airan is now an Assistant Professor of Radiology at Stanford University, where he is developing novel methods to interrogate and treat the brain, principally through the use of focused ultrasound and ultrasound-mediated focal drug delivery.

Beijing PINS Medical Equipment Co. Ltd. was established in 2008 and is located in Changpin Garden, Zhongguancun Science and Technology Park, Beijing, China. As an innovative high-tech enterprise with focus on neuromodulation, a variety of clinical products have been developed to date, which include stimulators for deep brain, vagus nerve, spinal cord and sacral nerve stimulation therapies. PINS Medical devotes itself to providing cutting edge treatments for patients who suffer from neurological disorders such as Parkinson's disease, epilepsy, chronic pain and uroclepsia.

As part of the "National Engineering Laboratory for neuromodulation", PINS Medical works in close cooperation with Tsinghua University and the numerous affiliated clinical centers, becoming a center of attraction for a wide range of professional talents in areas of clinical research, innovative R&D and business management. Since 2008, PINS Medical has developed rapidly in becoming a leading brand in neuromodulation within the Chinese market, due to the success of its creative research platform that efficiency links basic research, R&D of novel products, clinical testing and market entry. With an outstanding reputation as a high-tech healthcare corporation, PINS Medical has a primary mission for providing innovative, high-quality products and services for patients to improve quality of life.

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